Fused heteroaryl derivatives and their use as p38 kinase inhibitors

ABSTRACT

Compounds of formula (I): 
                         
are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38.

This application is the §371 national stage entry of PCT/GB2005/000266,filed 27 Jan. 2005.

This invention relates to novel compounds and their use aspharmaceuticals, particularly as p38 kinase inhibitors, for thetreatment of conditions or disease states mediated by p38 kinaseactivity or mediated by cytokines produced by the activity of p38kinase.

We have now found a group of novel compounds that are inhibitors of p38kinase.

According to the invention there is provided a compound of formula (I):

wherein

A is a fused 5-membered heteroaryl ring optionally substituted by up totwo substituents independently selected from C₁₋₆alkyl,—(CH₂)_(k)—C₃₋₇cycloalkyl, halogen, —CN, trifluoromethyl, —(CH₂)_(k)OR³,—(CH₂)_(k)CO₂R³, —(CH₂)_(k)NR³R⁴, —(CH₂)_(k)CONR³R⁴, —(CH₂)_(k)NHCOR³,—(CH₂)_(k)SO₂NR³R⁴, —(CH₂)_(k)NHSO₂R³, —(CH₂)_(k)SO₂(CH₂)_(m)R⁵, a 5- or6-membered heterocyclyl ring containing nitrogen optionally substitutedby C₁₋₂alkyl or —(CH₂)_(k)CO₂R³, and a 5-membered heteroaryl ringoptionally substituted by C₁₋₂alkyl;

A is a fused 5-membered heteroaryl ring substituted by —BR⁶, and A isoptionally further substituted by one substituent selected from —OR⁷,halogen, trifluoromethyl, —CN, —CO₂R⁷ and C₁₋₆alkyl optionallysubstituted by hydroxy;

A is a fused 5-membered heteroaryl ring substituted by—(CH₂)_(n)heterocyclyl wherein the heterocyclyl is a 5- or 6-memberedheterocyclic ring containing one or two heteroatoms independentlyselected from oxygen, sulfur and nitrogen optionally substituted by upto two substituents independently selected from oxo, C₁₋₆alkyl,—(CH₂)_(p)phenyl, —OR⁷, —(CH₂)_(p)CO₂R⁷, —NR⁷R⁸ and —CONR⁷R⁸, and A isoptionally further substituted by one substituent selected from —OR⁷,halogen, trifluoromethyl, —CN, —CO₂R⁷ and C₁₋₆alkyl optionallysubstituted by hydroxy; or

A is a fused 5-membered heteroaryl ring substituted by —(CH₂)_(q)aryl or—(CH₂)_(q)heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more substituents independently selected from oxo,C₁₋₆alkyl, halogen, —CN, trifluoromethyl, —OR⁹, —(CH₂)_(r)CO₂R¹⁰,—NR⁹R¹⁰, —(CH₂)_(r)CONR⁹R¹⁰, —NHCOR⁹, —SO₂NR⁹R¹⁰, —NHSO₂R⁹ and—S(O)_(s)R⁹, and

-   -   A is optionally further substituted by one substituent selected        from —OR⁷, halogen, trifluoromethyl, —CN, —CO₂R⁷ and C₁₋₆alkyl        optionally substituted by hydroxy;

R¹ is selected from methyl and chloro;

R² is selected from —NH—CO—R¹¹ and —CO—NH—(CH₂)_(t)—R¹²;

R³ is selected from hydrogen, C₁₋₆alkyl optionally substituted by up totwo OH groups, —(CH₂)_(k)—C₃₋₇cycloalkyl, —(CH₂)_(k)phenyl optionallysubstituted by R¹³ and/or R¹⁴ and —(CH₂)_(k)heteroaryl optionallysubstituted by R¹³ and/or R¹⁴,

R⁴ is selected from hydrogen and C₁₋₆alkyl, or

R³ and R⁴, together with the nitrogen atom to which they are bound, forma 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁵;

R⁵ is selected from C₁₋₆alkyl optionally substituted by up to threehalogen atoms, C₂₋₆alkenyl optionally substituted by phenyl,C₃₋₇cycloalkyl, heteroaryl optionally substituted by up to three R¹³and/or R¹⁴ groups, and phenyl optionally substituted by R¹³ and/or R¹⁴;

R⁶ is a C₃₋₆alkyl group substituted by at least two substituentsindependently selected from —OR¹⁶, —NR¹⁶R¹⁷, —CO₂R¹⁶, —CONR¹⁶R¹⁷,—NHCOR¹⁶ and —NHSO₂R¹⁶;

R⁷ and R⁸ are each independently selected from hydrogen and C₁₋₆alkyl;

R⁹ is selected from hydrogen, —(CH₂)_(u)—C₃₋₇cycloalkyl,—(CH₂)_(u)heterocyclyl, —(CH₂)_(u)aryl, and C₁₋₆alkyl optionallysubstituted by up to two substituents independently selected from —OR¹⁸and —NR¹⁸R¹⁹,

R¹⁰ is selected from hydrogen and C₁₋₆alkyl, or

R⁹ and R¹⁰, together with the nitrogen atom to which they are bound,form a 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁵;

R¹¹ is selected from hydrogen, C₁₋₆alkyl, —(CH₂)_(t)—C₃₋₇cycloalkyl,trifluoromethyl, —(CH₂)_(v)heteroaryl optionally substituted by R²⁰and/or R²¹, and —(CH₂)_(v)phenyl optionally substituted by R²⁰ and/orR²¹;

R¹² is selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, —CONHR²²,phenyl optionally substituted by R²⁰ and/or R²¹, and heteroaryloptionally substituted by R²⁰ and/or R²¹;

R¹³ and R¹⁴ are each independently selected from halogen, —CN,trifluoromethyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, —CONR²²R²³, —COR²⁴,—CO₂R²⁴, and heteroaryl, or

R¹³ and R¹⁴ are linked to form a fused 5-membered heterocyclyl ringcontaining one heteroatom selected from oxygen, sulfur and N—R¹⁵, or afused heteroaryl ring;

R¹⁵ is selected from hydrogen and methyl;

R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are each independently selected from hydrogen andC₁₋₆alkyl;

R²⁰ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(t)—C₃₋₇cycloalkyl,—CONR²²R²³, —NHCOR²³, halogen, —CN, —(CH₂)_(w)NR²⁵R²⁶, trifluoromethyl,phenyl optionally substituted by one or more R²¹ groups, and heteroaryloptionally substituted by one or more R²¹ groups;

R²¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl,and —(CH₂)_(w)NR²⁵R²⁶;

R²² and R²³ are each independently selected from hydrogen and C₁₋₆alkyl,or R²² and R²³, together with the nitrogen atom to which they are bound,form a 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁵, whereinthe ring may be substituted by up to two C₁₋₆alkyl groups;

R²⁴ is C₁₋₆alkyl;

R²⁵ is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(t)—C₃₋₇cycloalkyloptionally substituted by C₁₋₆alkyl,

R²⁶ is selected from hydrogen and C₁₋₆alkyl, or

R²⁵ and R²⁶, together with the nitrogen atom to which they are bound,form a 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁵;

R²⁷ is hydrogen or C₁₋₆alkyl;

B is selected from a bond, oxygen, NH and S(O)_(x);

X and Y are each independently selected from hydrogen, methyl andhalogen;

Z is selected from halogen, C₁₋₆alkyl and —OR²⁷;

k, m and w are each independently selected from 0, 1, 2 and 3;

n, q, r, s, t and x are each independently selected from 0, 1 and 2; and

u and v are each independently selected from 0 and 1;

or a pharmaceutically acceptable derivative thereof.

In one embodiment, A includes fused 5-membered heteroaryl ringscontaining up to two heteroatoms independently selected from oxygen,nitrogen and sulfur. In another embodiment, A includes fused 5-memberedheteroaryl rings containing up to two heteroatoms independently selectedfrom oxygen and nitrogen. In a further embodiment, A includes 5-memberedheteroaryl rings containing two heteroatoms independently selected fromoxygen and nitrogen, for example rings containing a nitrogen atom andone additional heteroatom selected from oxygen and nitrogen. Examples ofsuitable A groups include fused isoxazolyl, pyrazolyl and pyrrolyl ringssuch as those shown below:

Representative examples of A groups include fused isoxazolyl andpyrazolyl rings such as those shown below:

For example, A is a fused pyrazolyl ring:

Ring A may be optionally substituted by substituents located on anyposition on the ring. Preferably, ring A is substituted by onesubstituent.

A representative example of a compound of formula (I) is wherein A is afused isoxazolyl or pyrazolyl ring substituted in position (i) or (ii),for example position (ii), as shown below:

In one embodiment, A is optionally substituted by up to two substituentsindependently selected from C₁₋₄alkyl, in particular methyl;—(CH₂)_(k)—C₃₋₇cycloalkyl, in particular —(CH₂)_(k)-cyclopropyl;—(CH₂)_(k)OR³; —(CH₂)_(k)CO₂R³; —(CH₂)_(k)NR³R⁴; —(CH₂)_(k)CONR³R⁴;—(CH₂)_(k)NHCOR³; —(CH₂)_(k)SO₂(CH₂)_(m)R⁵; and a 5- or 6-memberedheterocyclyl ring containing nitrogen, in particular 4-piperidinyl,optionally substituted by C₁₋₂alkyl or —(CH₂)_(k)CO₂R³.

In another embodiment, A is substituted by —BR⁶.

In another embodiment, A is substituted by —(CH₂)_(n)heterocyclylwherein the heterocyclyl is a 5- or 6-membered heterocyclic ringcontaining one or two heteroatoms independently selected from oxygen,sulfur and nitrogen optionally substituted by up to two substituentsindependently selected from oxo, C₁₋₆alkyl, —(CH₂)_(p)phenyl, —OR⁷,—(CH₂)_(p)CO₂R⁷, —NR⁷R⁸ and —CONR⁷R⁸. Typically, the heterocyclyl is a5- or 6-membered heterocyclic ring containing one or two heteroatomsindependently selected from oxygen and nitrogen wherein the heterocyclylis optionally substituted by up to two substituents located on anyposition on the ring. For example, when the heterocyclyl contains asulfur atom, the sulfur atom may have up to two oxo substituents. In oneembodiment, the heterocyclyl is substituted by —(CH₂)_(n)phenyl.

In a further embodiment, A is substituted by —(CH₂)_(q)aryl or—(CH₂)_(q)heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more substituents independently selected from oxo,C₁₋₆alkyl, halogen, —CN, trifluoromethyl, —OR⁹, —(CH₂)_(r)CO₂R¹⁰,—NR⁹R¹⁰, —(CH₂)_(r)CONR⁹R¹⁰, —NHCOR⁹, —SO₂NR⁹R¹⁰, —NHSO₂R⁹ and—S(O)_(s)R⁹. Typically, the —(CH₂)_(q)aryl group is —(CH₂)_(q)phenyl andthe —(CH₂)_(q)heteroaryl group is a group wherein the heteroaryl is a 5-or 6-membered heteroaryl ring containing up to two heteroatomsindependently selected from oxygen and nitrogen. For example, the—(CH₂)_(q)heteroaryl group is a group wherein the heteroaryl is a 5- or6-membered heteroaryl ring containing one nitrogen atom, for examplepyridyl. The —(CH₂)_(q)aryl and —(CH₂)_(q)heteroaryl groups areoptionally substituted and the substituents may be located on anyposition on the aryl or heteroaryl. Preferably, the aryl is optionallysubstituted by one or two substituents independently selected fromC₁₋₆alkyl, in particular methyl, halogen, —CN, trifluoromethyl, —OR⁹,—NR⁹R¹⁰, —(CH₂)_(r)CONR⁹R¹⁰ and —S(O)_(s)R⁹. Preferably, the heteroarylis optionally substituted by one or two substituents independentlyselected from oxo and C₁₋₆alkyl, in particular methyl.

Representative examples include compounds of formula (I) wherein A issubstituted by —(CH₂)_(q)heteroaryl wherein the heteroaryl is a 5- or6-membered heteroaryl ring containing up to two heteroatomsindependently selected from oxygen and nitrogen and is optionallysubstituted by oxo. Further representative examples include compounds offormula (I) wherein A is substituted by —(CH₂)_(q)heteroaryl wherein theheteroaryl is a 5- or 6-membered heteroaryl ring containing up to twoheteroatoms independently selected from oxygen and nitrogen and isoptionally substituted by halogen or —OR⁹. For example, A is substitutedby —(CH₂)_(q)heteroaryl wherein the heteroaryl is a 6-memberedheteroaryl ring containing up to two heteroatoms independently selectedfrom oxygen and nitrogen, such as pyridyl, optionally substituted byoxo, halogen or —OR⁹.

In the compounds of formula (I), the Z group may be located on anyposition on the benzene ring as shown in formulae (IA), (IB) and (IC)below.

In one embodiment, the compound of formula (I) is a compound of formula(IB) wherein R¹, R², A, X, Y and Z are as hereinbefore defined.

A representative example of R¹ is methyl.

A representative example of R² is —CO—NH—(CH₂)_(t)—R¹².

In one embodiment, R³ selected from hydrogen; C₁₋₆alkyl optionallysubstituted by up to two OH groups, in particular methyl, ethyl,n-propyl, isopropyl, t-butyl or 2,2-dimethylpropyl optionallysubstituted by up to two OH groups; —(CH₂)_(k)—C₃₋₇cycloalkyl, inparticular —(CH₂)_(k)-cyclopropyl; —(CH₂)_(k)phenyl optionallysubstituted by R¹³ and/or R¹⁴; and —(CH₂)_(k)heteroaryl, in particularthiazolyl, optionally substituted by R¹³ and/or R¹⁴.

In one embodiment, R⁴ is selected from hydrogen and C₁₋₄alkyl such asmethyl.

Alternatively, R³ and R⁴, together with the nitrogen atom to which theyare bound, form a 5- or 6-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁵, in particular a pyrrolidinyl, piperidinyl, piperazinyl or4-methylpiperazinyl, or morpholinyl ring.

In one embodiment, R⁵ is selected from C₁₋₆alkyl optionally substitutedby up to three halogen atoms, in particular methyl, ethyl, n-propyl,isopropyl, n-butyl and n-hexyl optionally substituted by up to threehalogen atoms; C₂₋₆alkenyl optionally substituted by phenyl, inparticular ethenyl optionally substituted by phenyl; C₃₋₇cycloalkyl, inparticular cyclopropyl; heteroaryl optionally substituted by R¹³ and/orR¹⁴, in particular a 5-membered heteroaryl ring containing at least oneheteroatom selected from oxygen, nitrogen and sulfur such as furyl,thienyl, isoxazolyl, imidazolyl or pyrazolyl optionally substituted byup to three R¹³ and/or R¹⁴ groups; and phenyl optionally substituted byR¹³ and/or R¹⁴.

In one embodiment, R⁶ is a C₃₋₆alkyl group substituted by from two tofour substituents, for example two substituents, independently selectedfrom —OR¹⁶, —NR¹⁶R¹⁷ and —CO₂R¹⁶.

In one embodiment, R⁷ and R⁸ are independently selected from hydrogenand C₁₋₄alkyl.

In one embodiment, R⁹ is selected from hydrogen;—(CH₂)_(u)—C₃₋₇cycloalkyl, in particular —(CH₂)_(u)-cyclohexyl;—(CH₂)_(u)heterocyclyl, in particular wherein the heterocyclyl is a 5 or6 membered heterocyclyl containing one heteroatom selected from oxygen,nitrogen and sulfur such a tetrahydrofuran or tetrahydropyran; andC₁₋₆alkyl, in particular C₁₋₄alkyl such as methyl, ethyl, or n-propyl,optionally substituted by up to two substituents independently selectedfrom —OR¹⁸ and —NR¹⁸R¹⁹. A representative example of R⁹ is C₁₋₆alkyl, inparticular C₁₋₄alkyl such as methyl.

In one embodiment, R¹⁰ is hydrogen.

Alternatively, R⁹ and R¹⁰, together with the nitrogen atom to which theyare bound, form a 5- or 6-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁵, in particular morpholinyl.

In one embodiment, R¹¹ is a —(CH₂)_(v)heteroaryl optionally substitutedby R²⁰ and/or R²¹.

In one embodiment, R¹² is selected from C₃₋₇cycloalkyl, phenyloptionally substituted by R²⁰ and/or R²¹, and heteroaryl optionallysubstituted by R²⁰ and/or R²¹. A representative example of R¹² isC₃₋₆cycloalkyl, in particular cyclopropyl. A further representativeexample of R¹² is C₁₋₆alkyl, in particular C₁₋₄alkyl such as ethyl.

In one embodiment, R¹³ and R¹⁴ are each independently selected fromhalogen, in particular chlorine or fluorine; —CN; trifluoromethyl;nitro; C₁₋₄alkyl, in particular methyl, ethyl, n-propyl, isopropyl orn-butyl; C₁₋₄alkoxy, in particular methoxy; —CONR²²R²³; —COR¹⁵; —CO₂R¹⁵;and heteroaryl, in particular a 5-membered heteroaryl ring containing upto two heteroatoms independently selected from nitrogen and oxygen, forexample isoxazolyl.

Alternatively, R¹³ and R¹⁴ are linked to form a fused 5-memberedheterocyclyl ring containing one heteroatom selected from oxygen, sulfurand N—R¹⁵.

In one embodiment, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are each independently selectedfrom hydrogen and C₁₋₄alkyl.

In one embodiment, R²⁰ and R²¹ are each independently C₁₋₄alkoxy or—(CH₂)_(w)NR²⁵R²⁶.

In one embodiment, R²² and R²³ are each independently hydrogen orC₁₋₄alkyl.

In one embodiment, R²⁴ is C₁₋₄alkyl.

In one embodiment, R²⁵ and R²⁶, together with the nitrogen atom to whichthey are bound, form a 5- or 6-membered heterocyclic ring optionallyfurther containing one additional oxygen atom.

In one embodiment, R²⁷ is hydrogen or C₁₋₂alkyl.

In one embodiment, B is a bond.

In one embodiment, X and Y are each independently selected fromhydrogen, chlorine and fluorine. Representative examples of X includehydrogen and fluorine, for example hydrogen. A representative example ofY is hydrogen.

In one embodiment, Z is halogen, in particular fluorine.

In one embodiment, k and m are independently selected from 0, 1 and 2.

In one embodiment, n and r are independently 1.

In one embodiment, q and u are independently selected from 0 and 1. Arepresentative example of q is 0.

In one embodiment, s is 2.

A representative example of t is 0.

In one embodiment, v and w are independently 0.

It is to be understood that the present invention covers allcombinations of the embodiments and the particular and preferred groupsdescribed hereinabove. It is also to be understood that the presentinvention encompasses compounds of formula (I) in which a particulargroup or parameter, for example R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, k, m, p, r, s, t,u or w may occur more than once. In such compounds it will beappreciated that each group or parameter is independently selected fromthe values listed.

Particular compounds according to the invention include those mentionedin the Examples. Specific examples which may be mentioned include:

-   N-cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide;    and-   N-cyclopropyl-3-fluoro-5-[5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide;    and pharmaceutically acceptable derivatives thereof, for example    N-cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide    and pharmaceutically acceptable derivatives thereof.

As used herein, the term “pharmaceutically acceptable” means a compoundwhich is suitable for pharmaceutical use. Salts and solvates ofcompounds of the invention which are suitable for use in medicine arethose wherein the counterion or associated solvent is pharmaceuticallyacceptable. However, salts and solvates having non-pharmaceuticallyacceptable counterions or associated solvents are within the scope ofthe present invention, for example, for use as intermediates in thepreparation of other compounds of the invention and theirpharmaceutically acceptable salts and solvates.

As used herein, the term “pharmaceutically acceptable derivative”, meansany pharmaceutically acceptable salt, solvate or prodrug, e.g. ester, ofa compound of the invention, which upon administration to the recipientis capable of providing (directly or indirectly) a compound of theinvention, or an active metabolite or residue thereof. Such derivativesare recognizable to those skilled in the art, without undueexperimentation. Nevertheless, reference is made to the teaching ofBurger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent of teaching such derivatives. Preferred pharmaceuticallyacceptable derivatives are salts, solvates, esters, carbamates andphosphate esters. Particularly preferred pharmaceutically acceptablederivatives are salts, solvates and esters. Most preferredpharmaceutically acceptable derivatives are salts and esters, inparticular salts.

The compounds of the present invention may be in the form of and/or maybe administered as a pharmaceutically acceptable salt. For a review onsuitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared byusing a desired acid or base as appropriate. The salt may precipitatefrom solution and be collected by filtration or may be recovered byevaporation of the solvent.

Salts of the compounds of the present invention may, for example,comprise acid addition salts resulting from reaction of an acid with anitrogen atom present in a compound of formula (I). Salts encompassedwithin the term “pharmaceutically acceptable salts” refer to non-toxicsalts of the compounds of this invention. Suitable addition salts areformed from acids which form non-toxic salts and examples are acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydrogen phosphate, hydroiodide, hydroxynaphthoate,iodide, isethionate, lactate, lactobionate, laurate, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine,oxalate, oxaloacetate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, piruvate, polygalacturonate, saccharate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, triethiodide, trifluoroacetate and valerate.

Pharmaceutically acceptable base salts include ammonium salts such as atrimethylammonium salt, alkali metal salts such as those of sodium andpotassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases, including salts of primary,secondary and tertiary amines, such as isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexyl amine andN-methyl-D-glucamine.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. As used herein, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (inthis invention, a compound of formula (I) or a salt thereof) and asolvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include water, methanol, ethanol and acetic acid.Preferably the solvent used is a pharmaceutically acceptable solvent.Examples of suitable pharmaceutically acceptable solvents include water,ethanol and acetic acid. Most preferably the solvent used is water. Acomplex with water is known as a “hydrate”. Solvates of the compounds ofthe invention are within the scope of the invention.

As used herein, the term “prodrug” means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987; and in D. Fleisher, S. Ramon andH. Barbra “Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130, each of which are incorporated herein by reference.

Prodrugs are any covalently bonded carriers that release a compound offormula (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy or amine groups are bondedto any group that, when administered to a patient, cleaves to form thehydroxy or amine groups. Thus, representative examples of prodrugsinclude (but are not limited to) acetate, formate and benzoatederivatives of alcohol and amine functional groups of the compounds offormula (I). Further, in the case of a carboxylic acid (—COOH), estersmay be employed, such as methyl esters, ethyl esters, and the like.Esters may be active in their own right and/or be hydrolysable under invivo conditions in the human body. Suitable pharmaceutically acceptablein vivo hydrolysable ester groups include those which break down readilyin the human body to leave the parent acid or its salt.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl and t-butyl. A C₁₋₄alkyl group ispreferred, for example methyl, ethyl, isopropyl or t-butyl. The saidalkyl groups may be optionally substituted with one or more fluorineatoms for example, trifluoromethyl.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C₂₋₆alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl,2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl and1,1-dimethylbut-2-enyl.

As used herein, the term “alkoxy” refers to a straight or branched chainalkoxy groups containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy containing atleast 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy, or hexyloxy. A C₁₋₄alkoxy group is preferred, for examplemethoxy or ethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms whichmay optionally contain up to one double bond. For example,C₃₋₇cycloalkyl means a non-aromatic ring containing at least three, andat most seven, ring carbon atoms. Examples of “cycloalkyl” as usedherein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₃₋₆cycloalkyl group ispreferred, for example, cyclopropyl, cyclopentyl or cyclohexyl.

As used herein, the term “aryl” refers to an aromatic carbocyclic ringsuch as phenyl, biphenyl or naphthyl. Preferably the aryl is phenyl.

As used herein, the terms “heteroaryl ring” and “heteroaryl”, unlessotherwise defined, refer to a monocyclic 5- to 7-membered unsaturatedhydrocarbon ring containing at least one heteroatom independentlyselected from oxygen, nitrogen and sulfur. Preferably, the heteroarylring has five or six ring atoms. Examples of heteroaryl rings include,but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyland triazinyl. The said ring may be optionally substituted by one ormore substituents independently selected from C₁₋₆alkyl and oxy.

As used herein, the terms “heterocyclic ring” or “heterocyclyl”, unlessotherwise defined refer to a monocyclic 3- to 7-membered saturatedhydrocarbon ring containing at least one heteroatom independentlyselected from oxygen, nitrogen and sulfur. Preferably, the heterocyclylring has five or six ring atoms. Examples of heterocyclyl groupsinclude, but are not limited to, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl,tetrahydrofuranyl, and thiomorpholino. The said ring may be optionallysubstituted by one or more substituents independently selected fromC₁₋₆alkyl and oxy.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine orchlorine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

Separation of diastereoisomers or cis and trans isomers may be achievedby conventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. A stereoisomeric mixture of the agent mayalso be prepared from a corresponding optically pure intermediate or byresolution, such as H.P.L.C. of the corresponding racemate using asuitable chiral support or by fractional crystallisation of thediastereoisomeric salts formed by reaction of the corresponding racematewith a suitable optically active acid or base, as appropriate.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

A compound of formula (I) may be prepared by reacting a compound offormula (II)

in which A and Z are as hereinbefore defined and Hal is halogen, inparticular bromine, with a compound of formula (IIIA) or (IIIB)

in which R¹, R², X and Y are as hereinbefore defined,in the presence of a catalyst, for exampletetrakis(triphenylphosphine)palladium.

A compound of formula (II) wherein A is a fused pyrazolyl ring may, forexample, be prepared by reacting a compound of formula (IV)

in which Z, Hal, —(CH₂)_(q)aryl and —(CH₂)_(q)heteroaryl are ashereinbefore defined and Hal¹ is halogen, in particular fluorine,with a protected hydrazine derivative of formula (V)H₂NNH—P  (V)in which P is a protecting group such as Boc,followed by cyclisation in the presence of a base such as DBU.

A compound of formula (II) wherein A is a fused isoxazolyl ring may, forexample, be prepared by reacting a compound of formula (IV) ashereinbefore defined with hydroxylamine, followed by cyclisation in thepresence of a base such as DBU.

A compound of formula (IIIA) may be prepared by, for example, reacting acompound of formula (VI)

in which R¹, R², X and Y are as hereinbefore defined and Hal² ishalogen, in particular iodine,with bis(pinnacolato)diboron, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex (PdCl₂(ppdf)) and potassium acetate in asolvent such as DMF.

A compound of formula (IIIB) may be prepared by, for example, reacting acompound of formula (VI) as hereinbefore defined, with n-butyl lithiumand triisopropyl borate in a solvent such as THF.

When R² is —NH—CO—R¹¹, a compound of formula (VI) may be prepared byreacting an amine of formula (VII)

in which R¹, X, Y and Hal² are as hereinbefore defined,with an acid compound of formula (VIII)R¹¹CO₂H  (III)in which R¹¹ is as hereinbefore defined,under amide forming conditions.

Suitable amide forming conditions are well known in the art and includeadding a base such as DIPEA to a mixture of the amine of formula (VII),the acid of formula (VII), and HATU in a solvent such as DMF.

Alternatively, when R² is —CO—NH—(CH₂)_(t)—R¹², a compound of formula(VI) may readily be prepared from a corresponding acid compound offormula (IX)

in which R¹, X, Y and Hal² are as hereinbefore defined,by converting the acid to an activated form of the acid, for example theacid chloride, by treatment with, for example, thionyl chloride, andthen reacting the activated acid thus formed with an amine compound offormula (X)R¹²—(CH₂)_(t)—NH₂  (X)in which R¹² is as hereinbefore defined,under amide forming conditions.

Suitable amide forming conditions are well known in the art and includetreating a solution of the acid of formula (IX), or the activated formthereof, in for example DMF, with an amine of formula (X) in thepresence of a base such as triethylamine.

Alternatively, a further general method comprises final stagemodification of one compound of formula (I) into another compound offormula (I). Suitable functional group transformations for convertingone compound of formula (I) into another compound of formula (I) arewell known in the art and are described in, for instance, ComprehensiveHeterocyclic Chemistry II, eds. A. R. Katritzky, C. W. Rees and E. F. V.Scriven (Pergamon Press, 1996), Comprehensive Organic Functional GroupTransformations, eds. A. R. Katritzky, O. Meth-Cohn and C. W. Rees(Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry,eds. D. Barton and W. D. Ollis (Pergamon Press, Oxford, 1979), andComprehensive Organic Transformations, R. C. Larock (VCH PublishersInc., New York, 1989).

For example, one general method for preparing the compounds of formula(I) comprises the reaction set out in Scheme 1 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 2 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 3 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 4 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 5 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 6 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 7 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 8 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 9 below.

For example, a further method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 10 below.

Those skilled in the art will appreciate that in the preparation of thecompounds of the invention it may be necessary and/or desirable toprotect one or more sensitive groups in the molecule to preventundesirable side reactions. Suitable protecting groups for use accordingto the present invention are well known to those skilled in the art andmay be used in a conventional manner. See, for example, “Protectivegroups in organic synthesis” by T. W. Greene and P. G. M. Wuts (JohnWiley & sons 1991) or “Protecting Groups” by P. J. Kocienski (GeorgThieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealky silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate.

Whilst it is possible for the compounds of the present invention to beadministered as the raw chemical, the compounds of formula (I) and theirpharmaceutically acceptable derivatives are conveniently administered inthe form of pharmaceutical compositions eg when the agent is inadmixture with a suitable pharmaceutical excipient, diluent and/orcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice.

Thus, in another aspect of the invention, we provide a pharmaceuticalcomposition comprising at least one compound of formula (I) or apharmaceutically acceptable derivative thereof, in association with oneor more pharmaceutically acceptable excipients, diluents and/orcarriers. The excipient, diluent or carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

According to a further aspect, the invention provides a pharmaceuticalcomposition comprising, as active ingredient, at least one compound ofthe invention or a pharmaceutically acceptable derivative thereof, inassociation one or more pharmaceutically acceptable excipients, diluentsand/or carriers for use in therapy, and in particular in the treatmentof human or animal subjects suffering from a condition susceptible toamelioration by an inhibitor of p38 kinase.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of the compounds of thepresent invention and a pharmaceutically acceptable excipient, diluentand/or carrier (including combinations thereof).

There is further provided by the present invention a process ofpreparing a pharmaceutical composition, which process comprises mixingat least one compound of the invention or a pharmaceutically acceptablederivative thereof, together with a pharmaceutically acceptableexcipient, diluent and/or carrier.

The pharmaceutical compositions may be for human or animal usage inhuman and veterinary medicine and will typically comprise any one ormore of a pharmaceutically acceptable excipient, diluent or carrier.Acceptable carriers or diluents for therapetic use are well known in thepharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).The choice of pharmaceutical excipient, diluent or carrier can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as—or in addition to—the excipient, diluent or carrier anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s)and solubilising agent(s).

Preservatives, stabilisers, dyes and even flavouring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

For some embodiments, the agents of the present invention may also beused in combination with a cyclodextrin. Cyclodextrins are known to forminclusion and non-inclusion complexes with drug molecules. Formation ofa drug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described in WO91/11172, WO 94/02518 and WO 98/55148.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention may beprepared by processes known in the art, for example see WO 02/00196(SmithKline Beecham).

There may be different composition/formulation requirements dependent onthe different delivery systems. By way of example, the pharmaceuticalcomposition of the present invention may be formulated to be deliveredusing a mini-pump or by a mucosal route, for example, as a nasal sprayor aerosol for inhalation or ingestible solution, or parenterally inwhich the composition is formulated by an injectable form, for delivery,by, for example, an intravenous, intramuscular or subcutaneous route.Alternatively, the formulation may be designed to be delivered by bothroutes.

Where the agent is to be delivered mucosally through thegastrointestinal mucosa, it should be able to remain stable duringtransit though the gastrointestinal tract; for example, it should beresistant to proteolytic degradation, stable at acid pH and resistant tothe detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administeredby inhalation, in the form of a suppository or pessary, topically in theform of a lotion, solution, cream, ointment or dusting powder, by use ofa skin patch, orally in the form of tablets containing excipients suchas starch or lactose, or in capsules or ovules either alone or inadmixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavouring or colouring agents, or they can beinjected parenterally, for example intravenously, intramuscularly orsubcutaneously. For parenteral administration, the compositions may bebest used in the form of a sterile aqueous solution which may containother substances, for example enough salts or monosaccharides to makethe solution isotonic with blood. For buccal or sublingualadministration the compositions may be administered in the form oftablets or lozenges which can be formulated in a conventional manner.

The routes for administration (delivery) include, but are not limitedto, one or more of: oral (e.g. as a tablet, capsule, or as an ingestiblesolution), topical, mucosal (e.g. as a nasal spray or aerosol forinhalation), nasal, parenteral (e.g. by an injectable form),gastrointestinal, intraspinal, intraperitoneal, intramuscular,intravenous, intrauterine, intraocular, intradermal, intracranial,intratracheal, intravaginal, intracerebroventricular, intracerebral,subcutaneous, ophthalmic (including intravitreal or intracameral),transdermal, rectal, buccal, epidural and sublingual. It is to beunderstood that not all of the compounds need be administered by thesame route. Likewise, if the composition comprises more than one activecomponent, then those components may be administered by differentroutes.

The compounds of formula (I) and their pharmaceutically acceptable saltsand solvates may be formulated for administration in any suitablemanner. They may, for example, be formulated for topical administrationor administration by inhalation or, more preferably, for oral,transdermal or parenteral administration. The pharmaceutical compositionmay be in a form such that it can effect controlled release of thecompounds of formula (I) and their pharmaceutically acceptablederivatives. In a preferred embodiment, the agents of the presentinvention are delivered systemically such as orally, buccally orsublingually. A particularly preferred method of administration, andcorresponding formulation, is oral administration.

For oral administration, the pharmaceutical composition may take theform of, and be administered as, for example, tablets (includingsub-lingual tablets) and capsules (each including timed release andsustained release formulations), ovules, pills, powders, granules,elixirs, tinctures, emulsions, solutions, syrups or suspensions preparedby conventional means with acceptable excipients for immediate-,delayed-, modified-, sustained-, pulsed- or controlled-releaseapplications.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. The tablets may also contain excipientssuch as microcrystalline cellulose, lactose, sodium citrate, calciumcarbonate, dibasic calcium phosphate and glycine, disintegrants such asstarch (preferably corn, potato or tapioca starch), sodium starchglycollate, croscarmellose sodium and certain complex silicates, andgranulation binders such as polyvinylpyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, stearic acid, glyceryl behenate and talc may beincluded.

Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred excipients in this regard include lactose,starch, a cellulose, milk sugar or high molecular weight polyethyleneglycols. For aqueous suspensions and/or elixirs, the agent may becombined with various sweetening or flavouring agents, colouring matteror dyes, with emulsifying and/or suspending agents and with diluentssuch as water, ethanol, propylene glycol and glycerin, and combinationsthereof.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate, as, for example, starch or mannitol. Flavoring,preservative, dispersing and coloring agent can also be present.

Capsules can be made by preparing a powder mixture as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The compounds of the present invention can also be administered in theform of liposome emulsion delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula(I) in combination with a pharmaceutically acceptable carrier.

Likewise, the composition may also be administered in nasal, ophthalmic,otic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscular,inhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

If the compound of the present invention is administered parenterally,then examples of such administration include one or more of:intravenously, intraarterially, intraperitoneally, intrathecally,intraventricularly, intraurethrally, intrasternally, intracranially,intramuscularly or subcutaneously administering the agent; and/or byusing infusion techniques. For parenteral administration, thepharmaceutical composition may be given as an injection or a continuousinfusion (e.g. intravenously, intravascularly or subcutaneously). Thecompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. For administration byinjection these may take the form of a unit dose presentation or as amultidose presentation preferably with an added preservative.Alternatively for parenteral administration the active ingredient may bein powder form for reconstitution with a suitable vehicle. Forparenteral administration, the compound is best used in the form of asterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

The compositions of the present invention may be administered by directinjection.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively the composition may be formulated for topical application,for example in the form of ointments, creams, lotions, eye ointments,eye drops, ear drops, mouthwash, impregnated dressings and sutures andaerosols, and may contain appropriate conventional additives, including,for example, preservatives, solvents to assist drug penetration, andemollients in ointments and creams. Such topical formulations may alsocontain compatible conventional carriers, for example cream or ointmentbases, and ethanol or oleyl alcohol for lotions. Such carriers mayconstitute from about 1% to about 98% by weight of the formulation; moreusually they will constitute up to about 80% by weight of theformulation.

For application topically to the skin, the agent of the presentinvention can be formulated as a suitable ointment containing the activecompound suspended or dissolved in, for example, a mixture with one ormore of the following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water.

Alternatively, it can be formulated as a suitable lotion or cream,suspended or dissolved in, for example, a mixture of one or more of thefollowing: mineral oil, sorbitan monostearate, a polyethylene glycol,liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as tetrafluoroethane or heptafluoropropane, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges of e.g. gelatin for use in an inhaler or insufflator maybe formulated containing a powder mix of a compound of the invention anda suitable powder base such as lactose or starch.

Alternatively, the compound of the present invention can be administeredin the form of a suppository or pessary, or it may be applied topicallyin the form of a gel, hydrogel, lotion, solution, cream, ointment ordusting powder.

The compounds of the present invention may also be administered by thepulmonary or rectal routes. They may also be administered by the ocularroute. For ophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions generally are administered in an amounteffective for treatment or prophylaxis of a specific condition orconditions. Initial dosing in humans is accompanied by clinicalmonitoring of symptoms, such symptoms for the selected condition. Ingeneral, the compositions are administered in an amount of active agentof at least about 100 μg/kg body weight. In most cases they will beadministered in one or more doses in an amount not in excess of about 20mg/kg body weight per day. Preferably, in most cases, dose is from about100 μg/kg to about 5 mg/kg body weight, daily. For administrationparticularly to mammals, and particularly humans, it is expected thatthe daily dosage level of the active agent will be from 0.1 mg/kg to 10mg/kg and typically around 1 mg/kg. It will be appreciated that optimumdosage will be determined by standard methods for each treatmentmodality and indication, taking into account the indication, itsseverity, route of administration, complicating conditions and the like.The physician in any event will determine the actual dosage which willbe most suitable for an individual and will vary with the activity ofthe specific compound to be employed, the metabolic stability and lengthof action of that compound, age, weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination,severity of the particular condition and response of the particularindividual. The effectiveness of a selected actual dose can readily bedetermined, for example, by measuring clinical symptoms or standardanti-inflammatory indicia after administration of the selected dose. Theabove dosages are exemplary of the average case. There can, of course,be individual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention. For conditions ordisease states as are treated by the present invention, maintainingconsistent daily levels in a subject over an extended period of time,e.g., in a maintenance regime, can be particularly beneficial. For oraland parenteral administration to humans, the daily dosage level of theagent may be in single or divided doses.

In another aspect, the present invention provides a compound of formula(I) or a pharmaceutically acceptable derivative thereof, for use intherapy.

The compounds of the present invention are generally inhibitors of theserine/threonine kinase p38 and are therefore also inhibitors ofcytokine production which is mediated by p38 kinase. Within the meaningof the term “inhibitors of the serine/threonine kinase p38” are includedthose compounds that interfere with the ability of p38 to transfer aphosphate group from ATP to a protein substrate according to the assaydescribed below.

It will be appreciated that the compounds of the invention may beselective for one or more of the isoforms of p38, for example p38α,p38β, p38γ and/or p38δ. In one embodiment, the compounds of theinvention selectively inhibit the p38α isoform. In another embodiment,the compounds of the invention selectively inhibit the p38β isoform. Ina further embodiment, the compounds of the invention selectively inhibitthe p38α and p38β forms. Assays for determining the selectivity ofcompounds for the p38 isoforms are described in, for example, WO99/61426, WO 00/71535 and WO 02/46158.

It is known that p38 kinase activity can be elevated (locally orthroughout the body), p38 kinase can be incorrectly temporally active orexpressed, p38 kinase can be expressed or active in an inappropriatelocation, p38 kinase can be constitutively expressed, or p38 kinaseexpression can be erratic; similarly, cytokine production mediated byp38 kinase activity can be occurring at inappropriate times,inappropriate locations, or it can occur at detrimentally high levels.

Accordingly, the present invention provides a compound of formula (I) ora pharmaceutically acceptable derivative thereof for use in thetreatment or prophylaxis of a condition or disease state mediated by p38kinase activity or mediated by cytokines produced by the activity of p38kinase.

The present invention also provides a method for the treatment of acondition or disease state mediated by p38 kinase activity, or mediatedby cytokines produced by the activity of p38 kinase, in a subject whichcomprises administering to said subject a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablederivative thereof. The compound may be administered as a single orpolymorphic crystalline form or forms, an amorphous form, a singleenantiomer, a racemic mixture, a single stereoisomer, a mixture ofstereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention also provides a method of inhibiting cytokineproduction which is mediated by p38 kinase activity in a subject, e.g. ahuman, which comprises administering to said subject in need of cytokineproduction inhibition a therapeutic, or cytokine-inhibiting, amount of acompound of the present invention. The compound may be administered as asingle or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention treats these conditions by providing atherapeutically effective amount of a compound of this invention. By“therapeutically effective amount” is meant a symptom-alleviating orsymptom-reducing amount, a cytokine-reducing amount, acytokine-inhibiting amount, a kinase-regulating amount and/or akinase-inhibiting amount of a compound. Such amounts can be readilydetermined by standard methods, such as by measuring cytokine levels orobserving alleviation of clinical symptoms. For example, the cliniciancan monitor accepted measurement scores for anti-inflammatorytreatments. It will be appreciated that reference to treatment includesacute treatment or prophylaxis as well as the alleviation of establishedsymptoms.

The compounds of the present invention c an be administered to anysubject in need of inhibition or regulation of p38 kinase or in need ofinhibition or regulation of p38 mediated cytokine production. Inparticular, the compounds may be administered to mammals. Such mammalscan include, for example, horses, cows, sheep, pigs, mice, dogs, cats,primates such as chimpanzees, gorillas, rhesus monkeys, and, mostpreferably, humans.

Thus, the present invention provides methods of treating or reducingsymptoms in a human or animal subject suffering from, for example,rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema,allergic rhinitis, allergic conjunctivitis, adult respiratory distresssyndrome, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, silicosis, endotoxemia, toxic shocksyndrome, inflammatory bowel disease, tuberculosis, atherosclerosis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiplesclerosis, aneurism, stroke, irritable bowel syndrome, muscledegeneration, bone resorption diseases, osteoporosis, diabetes,reperfusion injury, graft vs. host reaction, allograft rejections,sepsis, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lymedisease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, cancer including breast cancer, colon cancer, lung canceror prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy and cancer including breast cancer, coloncancer, lung cancer and prostatic cancer, which comprises administeringto said subject a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease and cancer including breast cancer, colon cancer, lungcancer and prostatic cancer, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,chronic pulmonary inflammation, chronic obstructive pulmonary disease,neurodegenerative disease, Alzheimer's disease, Parkinson's disease andepilepsy which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from any type of pain includingchronic pain, rapid onset of analgesia, neuromuscular pain, headache,cancer pain, acute and chronic inflammatory pain associated withosteoarthritis and rheumatoid arthritis, post operative inflammatorypain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia,post-hepatic neuralgia, inflammatory neuropathies and migraine painwhich comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, in themanufacture of a medicament for use in the treatment of a condition ordisease state mediated by p38 kinase activity or mediated by cytokinesproduced by p38 kinase activity.

The compounds of formula (I) and their derivatives may be employed aloneor in combination with other therapeutic agents for the treatment of theabove-mentioned conditions. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention or apharmaceutically acceptable derivative thereof together with a furthertherapeutic agent.

In particular, in rheumatoid arthritis therapy, combination with otherchemotherapeutic or antibody agents is envisaged. Combination therapiesaccording to the present invention thus comprise the administration ofat least one compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof and at least one other pharmaceutically activeagent. The compound(s) of formula (I) or pharmaceutically acceptablesalt(s) or solvate(s) thereof and the other pharmaceutically activeagent(s) may be administered together or separately and, whenadministered separately, this may occur separately or sequentially inany order. The amounts of the compound(s) of formula (I) orpharmaceutically acceptable salt(s) or solvate(s) thereof and the otherpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. Appropriate doses will be readily appreciated bythose skilled in the art. It will be appreciated that the amount of acompound of the invention required for treatment will vary with thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or veterinarian. Examples of other pharmaceutically activeagents which may be employed in combination with compounds of formula(I) and their salts and solvates for rheumatoid arthritis therapyinclude: immunosuppressants such as amtolmetin guacil, mizoribine andrimexolone; anti-TNFα agents such as etanercept, infliximab, diacerein;tyrosine kinase inhibitors such as leflunomide; kallikrein antagonistssuch as subreum; interleukin 11 agonists such as oprelvekin; interferonbeta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis);interleukin 1 receptor antagonists such as anakinra; CD8 antagonistssuch as amiprilose hydrochloride; beta amyloid precursor proteinantagonists such as reumacon; matrix metalloprotease inhibitors such ascipemastat and other disease modifying anti-rheumatic drugs (DMARDs)such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine,auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention.

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the inventionor the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

EXAMPLES

The following Examples are illustrative embodiments of the invention,not limiting the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature.

LCMS was conducted on a column (3.3 cm×4.6 mm ID, 3 μm ABZ+PLUS), at aFlow Rate of 3 ml/min, Injection Volume of 5 μl, at room temperature andUV Detection Range at 215 to 330 nm. Solvent A: 10 mM Aqueous ammoniumacetate+0.1% formic acid. Solvent B: 95% Acetonitrile+0.05% formic acid.Gradient: 0% A/0.7 min, 0-100% A/3.5 min, 100% A1.1 min, 100-0% A/0.2min.

Intermediate 1 Z/E1-(4-Bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methanimine

A stirred solution of 1,4-dibromo-2,5-difluorobenzene (2.72 g) inanhydrous diethylether (50 ml) under nitrogen was cooled to −78° C. in adry-ice/acetone bath then treated with n-butyllithium (1.6M in hexanes,7.2 ml). The reaction mixture was stirred for 20 min and a solution of4-cyanopyridine (1.4 g) in diethylether (60 ml) was added dropwise. Theresulting mixture was stirred for a further 20 min then treated withsaturated aqueous ammonium chloride. The ether layer was separated,washed with brine, dried (sodium sulfate) and concentrated under vacuum.The crude product was purified on an SPE cartridge (silica) using acyclohexane/ethyl acetate gradient as eluant to give the title compoundas a colourless gum (1.50 g).

NMR: [δH CDCl₃] 10.35 (1H, s, minor), 10.35 (1H, s, major) 8.74 (2H, d,J=6 Hz, major and minor), 7.58 (2H, d, J=6 Hz, major), 7.48-7.42 (1H,m,), 7.40-7.03 (4H, m, major and minor).

Intermediate 2 1-(4-Bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methananone

A mixture of 1-(4-bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methanimine(Intermediate 1, 1.30 g) in methanol (20 ml) was treated with 0.5Mhydrochloric acid (1.5 ml). The reaction mixture was left at roomtemperature for 18 h then applied to an acidic ion exchange cartridge(SCX). Elution with methanol followed by 10% aqueous ammonia in methanolgave the title compound as a white solid (1.20 g).

LC-MS: Rt 2.96, MH⁺298/300.

Intermediate 3 1,1-Dimethylethyl(2Z)-2-[(4-bromo-2,5-difluorophenyl)(4-Pyridinyl)methylidene]hydrazinecarboxylate

A solution of 1-(4-bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methananone(Intermediate 2, 900 mg) and t-butylcarbazate (400 mg) in methanol (6ml) and acetic acid (0.5 ml) was stirred at reflux for 12 h. The mixturewas partitioned between water and ethyl acetate and the organic layerwas washed with water and brine, dried using a hydrophobic filter tubeand concentrated under vacuum. The residue was purified on an SPEcartridge (silica, 5 g) eluting with cyclohexane/ethyl acetate (9:1 to6:4) to give the title compound as a yellow gel (880 mg).

LC-MS: Rt 3.1/3.26, MH⁺412/414.

Intermediate 4 6-Bromo-5-fluoro-3-(4-pyridinyl)-1H-indazole

A solution of 1,1-dimethylethyl(2Z)-2-[(4-bromo-2,5-difluorophenyl)(4-pyridinyl)methylidene]hydrazinecarboxylate(Intermediate 3, 250 mg) and DBU (95 μ) in THF (3 ml) was stirred at150° C. in a microwave oven. After 30 min the mixture was partitionedbetween water and ethyl acetate and the organic layer was washed withwater and brine, dried using a hydrophobic filter tube and concentratedunder vacuum to give the title compound as an orange solid (150 mg).

LC-MS: Rt 2.7 min, MH⁺292/294.

Intermediate 5 Z/E (4-Bromo-2,5-difluorophenyl)(4-pyridinyl)methanoneoxime

A solution of Z/E1-(4-bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methanimine (Intermediate1, 150 mg) in ethanol (2 ml) was treated with a solution ofhydroxylamine hydrochloride (44 mg) and sodium acetate (50 mg) in water(0.4 ml) then stirred at reflux for 2 h. The ethanol was removed undervacuum and the residue was partitioned between water and ethyl acetate.The aqueous layer was re-extracted with ethyl acetate and the combinedorganic extracts were washed with brine, dried (sodium sulfate) andconcentrated under vacuum. The residue was purified on an SPE cartridge(silica, 2 g) eluting with cyclohexane/ethyl acetate (4:1 to 1:1) togive the title compound as a white foam (130 mg).

LC-MS: 2.83 min, 2.90 min, MH+313, 315.

Intermediate 6 6-Bromo-5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazole

A solution of Z/E (4-bromo-2,5-difluorophenyl)(4-pyridinyl)methanoneoxime (Intermediate 5, 124 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene(40 mg) in tetrahydrofuran (1.5 ml) was heated at 150° C. in a microwaveoven for 30 min. The solvent was removed under vacuum and the residuewas triturated with a small quantity of methanol to give the titlecompound as a cream coloured solid (32 mg).

LC-MS: Rt 3.21 min, MH+293, 295.

Intermediate 7 N-Methyl-N,6-bis(methyloxy)-3-pyridinecarboxamide

A mixture of 6-methoxynicotinic acid (0.784 g) in DMF (10 ml) wasstirred with N,O-dimethylhydroxylamine hydrochloride (0.5 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.16 g) and1-hydroxy-7-azabenzotriazole (50 mg). Triethylamine (1.67 ml) was addedand the reaction mixture was stirred at room temperature for 18 h. Thesolvent was removed under vacuum and the residue was partitioned betweenethyl acetate and water. The organic layer was separated using ahydrophobic filter tube and the solvent was evaporated to give the titlecompound as a colourless oil (0.86 g).

NMR: [δH CDCl₃] 8.65 (1H, s), 8.00 (1H, d), 6.76 (1H, d,), 3.99 (3H, s),3.58 (3H, s), 3.38 (3H, s).

Intermediate 8(2,5-Dibromo-3,6-difluorophenyl)[6-(methyloxy)-3-pyridinyl]methanone and(4-Bromo-2,5-difluorophenyl)[6-(methyloxy)-3-pyridinyl]methanone

A mixture of 1,4-dibromo-2,5-difluorobenzene (1.4 g) in THF (20 ml) wasstirred at −70° C. and treated with 1.6M BuLi in hexane (3.31 ml). After10 min the reaction mixture was treated withN-methyl-N,6-bis(methyloxy)-3-pyridinecarboxamide (Intermediate 7, 0.84g) in THF (10 ml). The reaction mixture was stirred at −70° C. for 90min, warmed to room temperature and stirred for 20 h. The mixture wascooled to −78° C., treated with saturated aqueous ammonium chloride thendiluted with ethyl acetate and further aqueous ammonium chloride. Theorganic layer was separated, washed with brine and dried using ahydrophobic filter tube. The residue was purified on a silica SPEcartridge eluting with a petroleum ether/ethyl acetate gradient (24:1 to1:1) to give the title compounds as a 2:3 mixture.

LC-MS: Rt: 3.33 min MH+327, 329 (minor)

LC-MS: Rt: 3.53 min MH+406, 408, 410 (major)

Intermediate 94,7-Dibromo-5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole and6-Bromo-5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole

A mixture of(2,5-dibromo-3,6-difluorophenyl)[6-(methyloxy)-3-pyridinyl]methanone-(4-bromo-2,5-difluorophenyl)[6-(methyloxy)-3-pyridinyl]methanone(Intermediate 8, 0.429 g), 1,1-dimethylethyl hydrazinecarboxylate (0.152g) and acetic acid (0.1 ml) in methanol (4.5 ml) was stirred at refluxfor 24 h. The solvent was evaporated and the resultant oil heated for 6h. The crude material in THF (4.5 ml) was treated with DBU (0.3 ml) thenheated in a sealed tube in a microwave oven at 150° C. for 30 min. Thesolvent was evaporated and the crude product was partitioned betweenethyl acetate and 0.5M aqueous hydrochloric acid. The organic layer waswashed with water and brine and concentrated under vacuum. The residuewas purified by using a silica SPE cartridge eluting with acyclohexane/ethyl acetate gradient (40:1 to 1:1) to give the titlecompounds as a 3:7 mixture (22 mg).

LC-MS: Rt: 3.4 min MH+322 (minor)

LC-MS: Rt: 3.68 min MH+400, 402 (major)

Intermediate 10N-Ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(1.3 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.44 g) and 3H-[1,2,3] 1-hydroxy-7-azabenzotriazole (0.077 g) was addedto a stirred solution of ethylamine in tetrahydrofuran (2M, 5 ml) inchloroform (30 ml) and the mixture was stirred for 24 h. The mixture waspoured into water, passed through a hydrophobic filter tube and theorganic phase was concentrated under vacuum. The residual solid waspurified on an SCX cartridge eluting with methanol to give the titlecompound as a pale yellow solid (1.36 g).

LC-MS: Rt 3.2 min.

Intermediate 11(4-Bromo-2,5-difluorophenyl)(6-chloro-3-pyridinyl)methanone

A mixture of 1,4-dibromo-2,5-difluorobenzene (1.36 g) in anhydrous THF(20 ml) and 1.6M n-BuLi in hexane (3.43 ml) was stirred at −78° C. undernitrogen for 20 min. The reaction mixture was added to6-chloro-N-methyl-N-(methyloxy)-3-pyridinecarboxamide (0.921 g) in THF(20 ml) and stirred at −78° C. The mixture was then stirred at −70° C.for 30 min allowed to warm to room temperature then cooled again to −70°C. and treated with 10% aqueous ammonium chloride. The reaction mixturewas warmed to room temperature and partitioned between ethyl acetate and10% aqueous ammonium chloride. The organic layer was separated using ahydrophobic filter tube and the solvent was removed under vacuum. Theresidue was purified using a silica SPE cartridge eluting with petroleumether/ethyl acetate (9:1 to 1:3) to give impure title compound (0.548g).

LC-MS: Rt 3.42 min, MH+332, 334.

Intermediate 12 6-Bromo-3-(6-chloro-3-pyridinyl)-5-fluoro-1H-indazole

Impure (4-bromo-2,5-difluorophenyl)(6-chloro-3-pyridinyl)methanone(0.548 g) in methanol (2 ml) was stirred with 1,1-dimethylethylhydrazinecarboxylate (0.152 g) and acetic acid (100 μl) for 20 h. Thecrude mixture was partitioned between sodium bicarbonate and chloroform.The organic layer was separated using a hydrophobic filter tube and thesolvent was removed under vacuum. The crude material in THF (1 ml) wastreated with DBU (0.358 ml) and heated in a sealed tube in a microwaveoven at 150° C. for 30 min. The reaction mixture was cooled andpartitioned between ethyl acetate and 0.5M aqueous hydrochloric acid.The organic layer was washed with water then brine then separated usinga hydrophobic filter tube. The organic phase was concentrated undervacuum and the residue was purifiedon a silica SPE cartridge (50 g)eluting with cyclohexane/ethyl acetate (100:0 to 0:100) to give thetitle compound (87 mg).

LC-MS: Rt 3.51 min, MH⁺326, 328, 330.

Example 1N-Cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide

A suspension of 6-bromo-5-fluoro-3-(4-pyridinyl)-1H-indazole(Intermediate 4, 20 mg),N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(21 mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueoussodium hydrogen carbonate (1M, 1 ml) in isopropanol (2 ml) was stirredin a microwave oven at 150° C. for 15 min. The mixture was partitionedbetween water and ethyl acetate and the organic layer was washed withwater and brine, dried using a hydrophobic filter tube and concentratedunder vacuum. The residue was purified on an SPE cartridge (silica, 5 g)eluting with cyclohexane:ethyl acetate (1:1 to 1:4) to give the titlecompound as a white solid (9.72 mg).

LC-MS: Rt 2.64, MH⁺387.

Example 2N-Cyclopropyl-3-[5-fluoro-3-(1-oxido-4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide

A solution ofN-cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide(Example 1, 9.3 mg) and m-CPBA (20 mg) in chloroform (2 ml) was stirredunder nitrogen at 60° C. for 1 h. The mixture was applied to an Isoluteamino cartridge (1 g) and eluted with chloroform/methanol (100:0 and90:10 to give the title compound as a yellow solid (5.5 mg).

LC-MS: Rt 2.58, MH⁺403.

Example 3N-Cyclopropyl-3-fluoro-5-[5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide

The procedure for Example 1 was followed using6-bromo-5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazole (Intermediate 6, 25mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronicacid (24 mg), tetrakis(triphenylphosphine)palladium(0) (1 mg) andsaturated aqueous sodium hydrogen carbonate (0.25 ml) in isopropanol (1ml). Elution of the SPE cartridge (silica, 1 g) with cyclohexane/ethylacetate (100:0 to 66:33) gave the title compound as a white solid (21mg).

LC-MS: Rt 3.26 min, MH+406.

Example 4N-Cyclopropyl-3-fluoro-5-[5-fluoro-3-(1-oxido-4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide

A solution ofN-cyclopropyl-3-fluoro-5-[5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide(Example 3, 12 mg) in chloroform (1 ml) under nitrogen was treated withM-CPBA (10 mg) and the mixture was stirred at 60° C. for 40 min. Furtherm-CPBA (10 mg) was added and stirring was continued for 1 h. Thesolution was applied to an Isolute amino cartridge (1 g) which waseluted with chloroform/methanol (100:0 to 90:10) to give a glass.Trituration using a small quantity of ether gave the title compound as awhite powder (9 mg).

LC-MS: Rt 2.85 min, MH+422.

Example 5N-Ethyl-3-{5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazol-6-yl}-4-methylbenzamide

A mixture of4,7-dibromo-5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole and6-bromo-5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole (2:1)(Intermediate 9, 20 mg),N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 10, 32 mg), 1M aqueous sodium bicarbonate (1 ml) andtetrakis(triphenylphosphine)palladium (6 mg) in isopropanol was heatedin a sealed vessel by microwave at 150° C. for 15 min. The reactionmixture was partitioned between chloroform and water and the organiclayer was separated using a hydrophobic filter tube. The organic layerwas concentrated under vacuum and the residue was purified by reversephase preparative HPLC to give the title compound (3 mg).

LC-MS: Rt 3.2 min, MH⁺404.

Example 63-[3-(6-Chloro-3-pyridinyl)-5-fluoro-1H-indazol-6-yl]-N-ethyl-4-methylbenzamide

A mixture of 6-bromo-3-(6-chloro-3-pyridinyl)-5-fluoro-1H-indazole(Intermediate 12, 16 mg),N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 10, 15 mg), 1M aqueous sodium bicarbonate (1 ml) andtetrakis(triphenylphosphine)palladium (0) (6 mg) in isopropanol (1 ml)was heated at 150° C. for 15 mins in a microwave oven. The reactionmixture was partitioned between chloroform and water and the organiclayer separated via hydrophobic filter tube. The organic layer wasevaporated and purified by mass directed preparative HPLC to give thetitle compound 1.64 mg.

LC-MS: 3.4 min, MH⁺409, 411.

ABBREVIATIONS

Ac₂O Acetic anhydride AcOH Acetic acid Boc t-Butoxycarbonyl BuLiButyllithium ^(t)BuONO t-Butyl nitrite CDI Carbonyldiimidazole DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DIPEA N,N-Diisopropylethylamine DMFDimethylformamide Et₂O Diethyl ether EtOH Ethanol h Hours Hal HalogenHATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HOBT 1-Hydroxybenzotriazole hydrate KOAc PotassiumAcetate m-CPBA 3-Chloroperbenzoic acid MeCN Acetonitrile MeOH Methanolmin Minutes Ms Mesyl NaO^(t)Bu Sodium tert-butoxide NaOEt SodiumEthoxide NCS N-Chlorosuccinimide PdCl₂(dppf)[1,1′-bis(Diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) Rt Retention Time SPE Solid phase extractionTHF Tetrahydrofuran

Biological Examples

The activity of compounds of formula (I) as p38 inhibitors may bedetermined by the following in vitro assays:

Fluorescence Anisotropy Kinase Binding Assay 1

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10×K_(i)) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be ≧1×K_(f). Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration. A typical protocol is:

All components dissolved in Buffer of final composition 62.5 mM HEPES,pH 7.5, 1.25 mM CHAPS, 1.25 mM DTT, 12.5 mM MgCl₂ 3.3% DMSO.

p38 Enzyme concentration: 12 nM

Fluorescent ligand concentration: 5 nM

Test compound concentration: 0.1 nM-100 μM

Components incubated in 30 μl final volume in NUNC 384 well blackmicrotitre plate until equilibrium reached (5-30 mins)

Fluorescence anisotropy read in LJL Acquest.

Definitions: K_(i)=dissociation constant for inhibitor binding

-   -   K_(f)=dissociation constant for fluorescent ligand binding

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.Fluorescence Anisotropy Kinase Binding Assay 2 (Macro Volume Assay)

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10×Ki) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be 2×Kf. Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration.

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Recombinant human p38α was expressed as a GST-tagged protein. Toactivate this protein, 3.5 μM unactivated p38α was incubated in 50 mMTris-HCl pH 7.5, 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1 mM sodiumvanadate, 10 mM MgAc, 0.1 mM ATP with 200 nM MBP-MKK6 DD at 30 degreesfor 30 mins. Following activation p38α was re-purified and the activityassessed using a standard filter-binding assay.

Protocol: All components are dissolved in buffer of composition 62.5 mMHEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl₂ with finalconcentrations of 12 nM p38α and 5 nM fluorescent ligand. 30 μl of thisreaction mixture is added to wells containing 1 μl of variousconcentrations of test compound (0.28 nM-16.6 μM final) or DMSO vehicle(3% final) in NUNC 384 well black microtitre plate and equilibrated for30-60 mins at room temperature. Fluorescence anisotropy is read inMolecular Devices Acquest (excitation 485 nm/emission 535 nm).

Definitions: Ki=dissociation constant for inhibitor binding

-   -   Kf=dissociation constant for fluorescent ligand binding        Fluorescence Anisotropy Kinase Binding Assay 3 (Micro Volume        Assay)

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10×Ki) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be 2×Kf. Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration.

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Recombinant human p38α was expressed as a GST-tagged protein. Toactivate this protein, 3.5 μM unactivated p38α was incubated in 50 mMTris-HCl pH 7.5, 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1 mM sodiumvanadate, 10 mM MgAc, 0.1 mM ATP with 200 nM MBP-MKK6 DD at 30 degreesfor 30 mins. Following activation p38α was re-purified and the activityassessed using a standard filter-binding assay.

Protocol: All components are dissolved in buffer of composition 62.5 mMHEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl₂ with finalconcentrations of 12 nM p38α and 5 nM fluorescent ligand. 6 μl of thisreaction mixture is added to wells containing 0.2 μl of variousconcentrations of test compound (0.28 nM-16.6 μM final) or DMSO vehicle(3% final) in Greiner 384 well black low volume microtitre plate andequilibrated for 30-60 mins at room temperature. Fluorescence anisotropyis read in Molecular Devices Acquest (excitation 485 nm/emission 535nm).

Definitions: Ki=dissociation constant for inhibitor binding

-   -   Kf=dissociation constant for fluorescent ligand binding        Results

The compounds described in the Examples were tested in at least one ofthe assays described above and had either IC₅₀ values of <10 μM orpK_(i) values of >6.

1. A compound of formula (I):

wherein A is a fused 5-membered heteroaryl ring containing up to twoheteroatom independently selected from oxygen, nitrogen or sulfursubstituted by —B¹R⁶, and A is optionally further substituted by onesubstituent selected from —OR⁷, halogen, trifluoromethyl, —CN, —CO₂R⁷and optionally substituted by hydroxy; or A is a fused 5-memberedheteroaryl ring containing up to two heteroatom independently selectedfrom oxygen, nitrogen or sulfur substituted by —(CH₂)_(n)heterocyclylwherein the heterocyclyl is a 5- or 6-membered heterocyclic ringcontaining one or two heteroatoms independently selected from oxygen,sulfur and nitrogen optionally substituted by up to two substituentsindependently selected from oxo, C₁₋₆alkyl, OR⁷, —NR⁷R⁸ and —CONR⁷R⁸,and A is optionally further substituted by one substituent selected from—OR⁷, halogen, trifluoromethyl, —CN, —CO₂R⁷ and C₁₋₆alkyl optionallysubstituted by hydroxy; or A is a fused 5-membered heteroaryl ringcontaining up to two heteroatom independently selected from oxygen,nitrogen or sulfur substituted by —(CH₂)_(q)aryl or —(CH₂)_(q)heteroarylwherein the aryl or heteroaryl is optionally substituted by one or moresubstituents independently selected from oxo, C₁₋₆alkyl, halogen, —CN,trifluoromethyl, —OR⁹, —(CH₂)_(r)CO₂R¹⁰, —NR⁹R¹⁰, —(CH₂)_(r)CONR⁹R¹⁰,—NHCOR⁹, —SO₂NR⁹R¹⁰, —NHSO₂R⁹ and —S(O)_(s)R⁹, and A is optionallyfurther substituted by one substituent selected from —OR⁷, halogen,trifluoromethyl, —CN, —CO₂R⁷ and C₁₋₆alkyl optionally substituted byhydroxy; R¹ is selected from methyl and chloro; R² is selected from—NH—CO—R¹¹ and —CO—NH—(CH₂)_(t)—R¹²; R⁶ is a C₃₋₆alkyl group substitutedby at least two substituents independently selected from —OR¹⁶,—NR¹⁶R¹⁷, —CO₂R¹⁶, —CONR¹⁶R¹⁷, —NHCOR¹⁶ and —NHSO₂R¹⁶; R⁷ and R⁸ areeach independently selected from hydrogen and C₁₋₆alkyl; R⁹ is selectedfrom hydrogen, —(CH₂)_(u)—C₃₋₇cycloalkyl, —(CH₂)_(u)heterocyclyl,—(CH₂)_(u)aryl, and C₁₋₆alkyl optionally substituted by up to twosubstituents independently selected from —OR¹⁸ and —NR¹⁸R¹⁹, R¹⁰ isselected from hydrogen and C₁₋₆alkyl, or R⁹ and R¹⁰, together with thenitrogen atom to which they are bound, form a 5- or 6-memberedheterocyclic ring optionally containing one additional heteroatomselected from oxygen, sulfur and N—R¹⁵; R¹¹ is selected from hydrogen,C₁₋₆alkyl, —(CH₂)_(t)—C₃₋₇cycloalkyl, trifluoromethyl,—(CH₂)_(v)heteroaryl optionally substituted by R²⁰ and/or R²¹, and—(CH₂)_(v)phenyl optionally substituted by R²⁰ and/or R²¹; R¹² isselected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, —CONHR²², phenyloptionally substituted by R²⁰ and/or R²¹, and heteroaryl optionallysubstituted by R²⁰ and/or R²¹; R¹⁵ is selected from hydrogen and methyl;R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are each independently selected from hydrogen andC₁₋₆alkyl; R²⁰ is selected from C₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(t)—C₃₋₇cycloalkyl, —CONR²²R²³, —NHCOR²³, halogen, —CN,—(CH₂)_(w)NR²⁵R²⁶, trifluoromethyl, phenyl optionally substituted by oneor more R²¹ groups, and heteroaryl optionally substituted by one or moreR²¹ groups; R²¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen,trifluoromethyl, and —CH₂)_(w)NR²⁵R²⁶; R²² and R²³ are eachindependently selected from hydrogen and C₁₋₆alkyl, or R²² and R²³,together with the nitrogen atom to which they are bound, form a 5- or6-membered heterocyclic ring optionally containing one additionalheteroatom selected from oxygen, sulfur and N—R¹⁵, wherein the ring maybe substituted by up to two C₁₋₆alkyl groups; R²⁵ is selected fromhydrogen, C₁₋₆alkyl and —(CH₂)_(t)—C₃₋₇cycloalkyl optionally substitutedby C₁₋₆alkyl, R²⁶ is selected from hydrogen and C₁₋₆alkyl, or R²⁵ andR²⁶, together with the nitrogen atom to which they are bound, form a 5-or 6-membered heterocyclic ring optionally containing one additionalheteroatom selected from oxygen, sulfur and N—R¹⁵; R²⁷ is hydrogen orC₁₋₆alkyl; B¹ is selected from a bond, oxygen, NH and S(O)_(x); X and Yare each independently selected from hydrogen, methyl and halogen; Z isselected from halogen, C₁₋₆alkyl and —OR²⁷; m and w are eachindependently selected from 0, 1, 2 and 3; n, q, r, s, t and x are eachindependently selected from 0, 1 and 2; and u and v are eachindependently selected from 0 and 1; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1 wherein A is a fused5-membered heteroaryl ring containing up to two heteroatomsindependently selected from oxygen and nitrogen.
 3. A compound accordingto claim 1 wherein A is substituted by —CH₂)_(q)aryl or—(CH₂)_(q)heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more substituents independently selected from oxo,C₁₋₆alkyl, halogen, —CN, trifluoromethyl, —OR⁹, —(CH₂)_(r)CO₂R¹⁰,—NR⁹R¹⁰, —(CH₂)_(r)CONR⁹R¹⁰, —NHCOR⁹, —SO₂NR⁹R¹⁰, —NHSO₂R⁹ and—S(O)_(s)R⁹.
 4. A compound according to claim 1 wherein R¹ is methyl. 5.A compound according to claim 1 wherein R² is —CO—NH—(CH₂)_(t)—R¹².
 6. Acompound according to claim 1 wherein X is hydrogen or fluorine.
 7. Acompound according to claim 1 which isN-Cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide;N-Cyclopropyl-3-[5-fluoro-3-(1-oxido-4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide;N-Cyclopropyl-3-fluoro-5-[5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide;N-Cyclopropyl-3-fluoro-5-[5-fluoro-3-(1-oxido-4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide;N-Ethyl-3-{5-fluoro-3-[6-(methyloxy)-3-pyridinyl]-1H-indazol-6-yl}-4-methylbenzamide;3-[3-(6-Chloro-3-pyridinyl)-5-fluoro-1H-indazol-6-yl]-N-ethyl-4-methylbenzamide;or a pharmaceutically acceptable salt thereof.
 8. A compound—which is:N-cyclopropyl-3-[5-fluoro-3-(4-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide;orN-cyclopropyl-3-fluoro-5-[5-fluoro-3-(4-pyridinyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide;or a pharmaceutically acceptable derivative thereof.
 9. A pharmaceuticalcomposition comprising at least one compound as claimed in claim 1, or apharmaceutically acceptable derivative thereof, in association with oneor more pharmaceutically acceptable excipients, diluents and/orcarriers.
 10. A process for preparing a compound of formula (I) asclaimed in claim 1, or a pharmaceutically acceptable salt thereof, whichcomprises (a) reacting a compound of formula (II)

in which A is defined in claim 1 and Hal is halogen, with a compound offormula (IIIA) or (IIIB)

in which R¹, R², X and Y are as defined in claim 1, in the presence of acatalyst, or (b) final stage modification of one compound of formula (I)as defined in claim 1 to give another compound of formula (I) as definedin claim
 1. 11. A compound according to claim 3 wherein A is substitutedby —CH₂)_(q)heteroaryl wherein the heteroaryl is optionally substitutedby one or more substituents independently selected from oxo, C₁₋₆alkyl,halogen, —CN, trifluoromethyl, —OR⁹, —(CH₂)_(r)CO₂R¹⁰, NR⁹R¹⁰,—(CH₂)_(r)CONR⁹R¹⁰, —NHCOR⁹, —SO₂NR⁹R¹⁰, —NHSO₂R⁹ and —S(O)_(s)R⁹.
 12. Acompound according to claim 11 wherein R¹ is methyl.
 13. A compoundaccording to claim 11 wherein R² is —CO—NH—(CH₂)_(t)—R¹².
 14. A compoundaccording to claim 11 wherein X is hydrogen or fluorine.
 15. A compoundaccording to claim 11 wherein the 5-membered ring fused to the phenylring is an indazole.
 16. A compound according to claim 11 wherein theheteroaryl is a 5- or 6-membered heteroaryl ring containing up to twoheteroatoms independently selected from oxygen and nitrogen.
 17. Acompound according to claim 16 wherein the heteroaryl ring is a pyridyl.18. A compound according to claim 17 wherein q is
 0. 19. A compoundaccording to claim 1 wherein Z is a halogen.
 20. A compound according toclaim 1 wherein the 5-membered ring A fused to the phenyl ring is anoptionally substituted isoxazolyl, indazole, pyrazolyl or pyrrolyl. 21.A compound according to claim 20 wherein the 5-membered ring A fused tothe phenyl ring is an optionally substituted isoxazolyl.
 22. A compoundaccording to claim 20 wherein the 5-membered ring A fused to the phenylring is an optionally substituted indazole.